The 2-((2,6 dichlorophenyl)amino)phenyl acetic (diclofenac) acid (CAS No 15307-86-5) is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic, anti-inflammatory and antipyretic activity.
Diclofenac and the salts thereof are frequently used in human medicine in the form of coated tablets or oral capsules.
The salts are characterized by their bitter, unpleasant taste and strong astringency.
Also, they generally have significant side effects such as nausea, epigastric pains, vomiting, diarrhoea and gastric irritation, with medical surveillance being particularly advisable for patients with a history of peptic ulcers and gastrointestinal bleeding.
Preventing the above-mentioned adverse and frequent gastrointestinal side effects of nonsteroidal anti-inflammatory drugs is particularly important. In that it is independent of the treatment time and more important in risk groups such as                Patients over 60 years old        Patients with a history of peptic ulcers        Patients treated with corticosteroids or anticoagulants        Patients with a history of alcoholism and/or smoking                    (Arya N., Rossos P. G., Geriatrics & Agentes 2002; 5 (10); 28-31).                        
Consequently, it is necessary to have an orally administered composition that includes diclofenac or one of the salts thereof, but with the particular characteristic of providing local mucus protection in the stomach, as well as levels of diclofenac or convenient anti-inflammatory and analgesic activity.
Historically, literature has highlighted the aggressiveness of nonsteroidal anti-inflammatory drugs. It has even shown that the simultaneous use of two pharmaceutical compositions, each containing a proton pump inhibitor (omeprazole) and a nonsteroidal anti-inflammatory drug, reduces the occurrence of ulcers in patients (Hawkey C. J. et al; N. Engl., J. Med. 1998; 338; 727-34: Yeomans N. D. et al, N. Engl., J. Med 1998; 338, 719-26). Ratifying the need to protect the gastric mucus from the considerable aggressiveness caused by nonsteroidal anti-inflammatory drugs.
Pharmaceutical technology has resolved numerous problems associated with producing oral pharmaceutical compositions using techniques applied previously to the pure active ingredients containing them.
The methods used with the pure active ingredients enable: protecting substances against humidity, preventing oxidation, masking the taste and smell of substances which, in organoleptic terms, are unpleasant, improving the stability of pharmaceutical compositions, modifying the release speed of active ingredients and others.
The methods used have been numerous, heterogeneous and dependent on the physical-chemical properties of the active ingredient in question.
In a non-limiting manner, they can be classified as a) Physical-chemical methods, such as for example, microencapsulation through solvent evaporation; b) Chemical, via gelation of the support material, and others; c) Mechanical, with fluid bed coating, and others.
The number of explored alternatives has been very high. So, for example:
I) One of the alternatives described relates to microencapsulation. The microcapsules are solid products made up of spherical, quasi spherical or irregular shaped polymers, sized between 100 and approximately 1000 micron and containing ingredients that are pharmacologically active.
Generally, a microencapsulation method with optimum characteristics requires the strict control of a large number of parameters.                J. B. Deasy (J. Microencapsulation, 1994, Vol. II, No 5, 487-505) and A. K. Dash (J. Microencapsulation, 1997, Vol. 14, No 1, 101-112) have described some factors that condition the characteristics or properties of the products obtained by microencapsulation such as: size, content and release speed of the substances with pharmacological activity that they contain. The microcapsule characteristics or properties are associated with several factors. For example:                    a) The production method,            b) Composition,            c) The solubility of the active ingredient,            d) The formation time.                        For pharmaceutical use, the formation of the microcapsules obtained from alginic acid, is interesting because of the non toxic nature of the alginic acid, which is non-mutagenic, or immunogenic, and also because of its particular ability to not react with the pharmacologically active ingredients.        By incorporating an aqueous solution of sodium alginate in another solution, also aqueous, of calcium chloride, it is possible to obtain microcapsules via gelation. But the microcapsules that are obtained using this process, usually tend to join together and their size is frequently larger than 1 mm.        
II) Another different alternative was the obtention of microparticles described by M. F. Al-Omran et al (J. Microencapsulation 2002, Vol. 19, No. 1, 45-52). It is a method intended to mask the unpleasant taste of diclofenac sodium via evaporation of the solvent contained in the active ingredient and other components. The method is complex and involves two general steps:                A) In the first step, diclofenac sodium cores are prepared via the suspension of diclofenac sodium in acetone-b-hexane, lactose and avicel and the gradual addition of water up to agglomeration.        B) In the second step the microcapsules are prepared by adding the diclofenac sodium cores to a solution of ethyl cellulose in toluene, under stirring (1000 r.p.m.). Beforehand, diethylphlalate or polyethylene glycol 600 are added as plastifying agents (20 to 40% w/w vis-à-vis the weight of ethyl cellulose and petrol ether) gradually until the solution starts to turn cloudy. Also 2% magnesium stearate is added. The microcapsules that are formed are filtered and dried over 24 hours.        
The method suffers from various practical drawbacks:                a) It requires two general steps and each one conditions the final characteristics of the microcapsules.        b) It uses organic solvents, which must be completely removed before preparing pharmaceutical formats for human use.        c) The diclofenac content of the microcapsules obtained is very irregular and can vary between 23.1 and 60.1% according to the nature of the cores that are used (diclofenac powder or spherical cores containing diclofenac).        
To summarise, it is not a very practical method.
III) In 1998 M. J. Fernandez et al. (International Journal of Pharmaceutical 163 (1998); 23-24) described the production of enteric microcapsules with a heterogeneous composition containing diclofenac, hydroxy ethyl pyrrolidine, calcium alginate and Eudragit L30D and others which, apart from the diclofenac salt, contain alginate and chitosan.
The method described is not very practical in that for both cases it requires incubating at ambient temperature (22° C.) for 24 hours and drying at ambient temperature another 24 hours. The authors highlight that it is necessary to study the influence of various factors (molecular weight of chitosan, chitosan/alginate ratio and interaction of diclofenac salt-chitosan); consequently, it is not a defined method, likely to be applicable to industry. Neither do they describe the production of pharmaceutical compositions.
IV) In 2009 V. N. Deshmukh et al (Researh J. Pham and Tech 2 (2) April-June 2009-p. 324-327) described the production and control of heterogeneous microcapsules comprising calcium alginate and a hydrophilic polymer of the Locus bean type and Xanthan gum with extended release—they do not produce pharmaceutical compositions and the microcapsules obtained suffer from the drawback that the total release of the content requires virtually 12 hours.
V) The literature also describes other different methods for forming microparticles containing diclofenac or the salts thereof. For example, via pelletizing. The pellets obtained are used in the production of pharmaceutical compositions. For example, U.S. Pat. No. 5,800,836 reveals a pharmaceutical formula in the form of delayed action pellets or U.S. Pat. No. 5,711,967 also mentions a pharmaceutical formula in the form of delayed action pellets comprising diclofenac sodium and others.
In all the cases mentioned in the literature for the production of pellets or microgranules via extrusion and spheronization, complex, industrial equipment is used. For example, Marumerizer (Luwa) or CF-Granulator (Vector).
VI) Another different technological alternative for manufacturing useful particles for producing pharmaceutical compositions mentioned in the technical literature includes using neutral starch cores, sugar, microcrystalline cellulose or other substances that are small in size and are covered by atomization with a solution or suspension containing the active ingredient (diclofenac or the salts thereof) together with other components like polymers, fixing agents, plastifying agents, colouring agents and known additives for pharmaceutical use.
This methodology, although interesting, suffers from the drawback of requiring the use of high technology equipment like a fluid bed dryer for atomisation which, generally includes a Wurster system that obliges the movement of the particles and enables them to be coated uniformly with spray. Expensive industrial system that is neither easily nor quickly implemented in industry due to the high number of variables involved, including, the number of components in the coating solution or suspension, flow speed, air pressure, operating temperature, etc. Producing the coated microgranules using this methodology is very complex because of the significant number of variables to be considered in each case and also its industrial implementation is very complex in the scale increase from small scale laboratory to normal production scale. An operation that can determine the success or failure of the implementation.
VII) Patent Application AR No P040100731 (19 May 2004) published on 14 Sep. 2005 under number AR 44.398 Al claims a method of producing heterogeneous microcapsules whose active ingredient is optionally sodium diclofenac, ibuprofen, famotidine or acetylsalicylic acid characterized in that the active ingredient is added dissolved or in suspension (with a particle size between 20 and 120 micron) to a solution containing sodium bicarbonate, sodium alginate and an appropriate surfactant, and the suspension that is formed is dispersed under stirring in an aqueous solution of calcium chloride, producing the formation of microcapsules that separate from each other or are filtered, without previous drying, and are added to an aqueous solution made up of coating agents including sucralose, colouring agent, lactose, hydroxypropyl methylcellulose, triacetin and titanium oxide (see page 5, line to page 6, line 6, claim 9) which confer enteric behaviour and the ability to correct the taste of the microcapsules formed.
The microcapsules obtained have a heterogeneous composition due to the coating applied to them. Their active ingredient content is between 30 and 55% according to the nature of the active ingredient and the enteric coating used in the method.
However this process requires that the shape of the microcapsules obtained be almost perfect spheres with an even particle size so as to obtain a uniform coating.
Consequently, there is a technical void which makes it necessary to provide a practical method for producing microcapsules of diclofenac or one of the salts thereof preferably with a homogeneous composition, that is, which only include in their composition calcium alginate without the need of the enteric coatings aggregate, and which ensures that the microcapsules obtained have, among others, the following characteristics: a) high active ingredient content; b) which do not release the active ingredient at the average stomach acid pH; c) which immediately release the active ingredient they contain at the average intestine pH; d) and physical strength and sufficient stability to enable the production of the chosen pharmaceutical composition; e) with sufficient plasticity to produce tablets and chewable tablets, which thanks to said plasticity prevent the microcapsules being broken by the pressure applied during the production of these compositions; f) that the microcapsules obtained mask partially or wholly the unpleasant taste of diclofenac or the salts thereof to contribute to the patient's acceptability of the pharmaceutical composition containing them, the indicated dosage and consequently the fulfilment of the treatment; g) that due to their stability they also enable the association with other active ingredients and, in particular, with proton pump inhibitors in the form of pellets, with omeprazole pellets, esomeprazole pellets and lanzoprazole pellets being chosen; h) that their composition only includes sodium alginate obtained via gelation with a soluble calcium salt, and no other additional components.
And above all, that they have the particular characteristic of providing local mucus protection to the stomach and also anti-inflammatory, analgesic activity and appropriate levels of diclofenac.